Macular degeneration is a clinical term that is used to describe a variety of diseases that are all characterized by a progressive loss of central vision associated with abnormalities of Bruch's membrane, the neural retina and the retinal pigment epithelium. Clinically, macular degeneration is associated with progressive diminution of visual acuity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity (Steinmetz, et al., 1993; Brown & Lovie-Kitchin, 1983; Brown, et al., 1986; Sunness, et al., 1985; Sunness, et al., 1988; Sunness, et al., 1989; Eisner, et al., 1987; Massof, et al., 1989; Chen, et al., 1992). When the manifestations of macular degeneration occur after age 50 years, the disorder is termed age-related macular degeneration (AMD).
AMD is the leading cause of legal blindness in North America and Western Europe (Hyman, 1992) and has become a significant health problem as the percentage of individuals above the age of 50 increases. In the Beaver Dam, Wis. population, the incidence of AMD was estimated to be 9.2% for persons over the age of 40 (Klein, et al., 1995). The Framingham Eye Study found the overall incidence of AMD to be 8.8%, with a 27.9% incidence in the 75–85 year old population (Kahn, et al., 1977; Leibowitz, et al., 1980). In an Australian study, 18.5% of those over age 85 were estimated to be afflicted with AMD (O'Shea, 1996). Variations in estimated incidence are likely a result of the use of different criteria for a diagnosis of AMD in different studies, or they may result from different risk factors among the various populations studied.
Two principal clinical manifestations of AMD have been described, both of which can occur in the same patient (Green and Key, 1977). They are referred to as the dry, or atrophic, form, and the wet, or exudative, form (Sarks and Sarks, 1989; Elman and Fine, 1989; Kincaid, 1992). In the dry form, the RPE and retina degenerate without coincident neovascularization. The region of atrophy that results is referred to as geographic atrophy. While atrophic AMD is typically considered less severe than the exudative form because its onset is less sudden, no treatment is effective at halting or slowing its progression. In the less common, but more devastating, exudative form, neovascular “membranes” derived from the choroidal vasculature invade Bruch's membrane, leak, and often cause detachments of the RPE and/or the neural retina (Elman and Fine, 1989). This event can occur over a short period of time and can lead to rapid and permanent loss of central vision. If one eye is affected, there is a high degree of probability that the second eye will develop a choroidal neovascular membrane within five years of the initial event (Macular Photocoagulation Study, 1977). Important clinical signs of neovascular AMD include gray-green neovascular membranes, dome-shaped RPE detachments, and disciform scars (caused by proliferation of fibroblasts and retinal glial cells) which are best visualized by their hyperfluorescence on fluorescein angiography (Elman and Fine, 1989). A number of studies have demonstrated that the presence of macular drusen is a strong risk factor for the development of both atrophic and neovascular AMD (Gass, 1973; Lovie-Kitchin and Bowman, 1985; Lewis, et al., 1986; Sarks, 1980; Sarks, 1982; Small, et al., 1976; Sarks, et al., 1985; Vinding, 1990; Bressler, et al., 1994; Bressler, et al., 1990; Macular Photocoagulation Study). Pauleikhoff, et al. (1990) demonstrated that the size, number, density and extent of confluency of drusen are important determinants of the risk of AMD. The risk of developing neovascular complications in patients with bilateral drusen has been estimated at 3–4% per year (Mimoun, et al., 1990). A recent report from the Macular Photocoagulation Study Group shows a relative risk of 2.1 for developing choroidal neovascularization in eyes possessing 5 or more drusen, and a risk of 1.5 in eyes with one or more large drusen (Macular Photocoagulation Study, 1997). The correlation between drusen and AMD is significant enough that many investigators and clinicians refer to the presence of soft drusen in the macula, in the absence of vision loss, as “early AMD” (Midena, et al., 1997; Tolentino, et al., 1994), or “early age-related maculopathy” (Bird, et al., 1995). In addition to macular drusen, Lewis et al. (1986) found that the degree of extramacular drusen is also a significant risk factor for the development of AMD.
A number of population-based studies indicate that AMD has a genetic component, based upon the examination of the rates of AMD in different racial groups and the degree of familial aggregation of AMD (Hyman, et al., 1983). For example, Caucasians appear to be at greater risk than individuals of Hispanic origin (Cruickshanks, et al., 1997). In addition, a black population on Barbados had a lower incidence of advanced AMD than the local Caucasian population (Schachat, et al., 1995). Studies involving twins and other siblings have demonstrated that, the more related two individuals are, the more likely they are to be at the same risk of developing AMD (Heiba, et al., 1994; Klein, et al., 1994; Meyers and Zacchary, 1988; Meyers, 1994; Meyers, et al., 1995; Piguet, et al., 1993; Seddon, et al., 1997; Silvestri, et al., 1994). These findings suggest that heredity contributes significantly to an individual's risk of developing AMD, but the gene(s) responsible have not been identified. Although a recent report suggested that mutations in the photoreceptor ABCR rim protein cause up to 15% of AMD cases in the United States (Allikmets, et al., 1997), more recent data has shown this not to be the case (De La Paz, et al., 1998; Stone et al., 1998). Thus, no gene accounting for all AMD has been identified.
Other maculopathies, typically with an earlier onset of symptoms than AMD, have been described. These include North Carolina macular dystrophy (Small, et al., 1993), Sorsby's fundus dystrophy (Capon, et al., 1989), Stargardt's disease (Parodi, 1994), pattern dystrophy (Marmor and Byers, 1977), Best disease (Stone, et al., 1992), dominant drusen (Deutman and Jansen, 1970), and radial drusen (“malattia leventinese”) (Heon, et al., 1996). Several of these inherited disorders, including those that map to distinct chromosomal loci or for which the genes have been identified, are characterized by the presence of drusen (or other extracellular deposits in the subRPE space). Based on this information, it is likely that: (1) AMD is not a single, genetic disease, since different diseases with distinct chromosomal loci share morphologic differences (Holz, et al., 1995a; Mansergh et al., 1995; and (2) that drusen may develop as a result of a biological pathway induced by a variety of different insults, genetic or otherwise. AMD may actually be several diseases most of which are genetic, with environmental factors play some role in its development.
A number of gene loci have been reported as indicating a predisposition to macular degeneration: 1p21–q13, for recessive Stargardt's disease or findus flavi maculatus (Allikmets, R. et al. Science 277:1805–1807, 1997; Anderson, K. L. et al., Am. J. Hum. Genet. 55:1477, 1994; Cremers, F. P. M. et al., Hum. Mol. Genet. 7:355–362, 1998; Gerber, S. et al., Am. J. Hum. Genet. 56:396–399, 1995; Gerber, S. et al., Genomics 48:139–142, 1998; Kaplan, J. et al., Nat. Genet. 5:308–311, 1993; Kaplan, J. et al., Am. J. Hum. Genet. 55:190, 1994; Martinez-Mir, A. et al., Genomics 40:142–146, 1997; Nasonkin, I. et al., Hum. Genet. 102:21–26, 1998; Stone, E. M. et al., Nat. Genet. 20:328–329, 1998); 1q25–q31, for recessive age related macular degeneration (Klein, M. L. et al., Arch. Ophthalmol. 116:1082–1088, 1988); 2p16, for dominant radial macular drusen, dominant Doyne honeycomb retinal degeneration or Malattia Leventinese (Edwards, A. O. et al., Am. J. Ophthalmol. 126:417–424, 1998; Heon, E. et al., Arch. Ophthalmol. 114:193–198, 1996; Heon, E. et al.,. Invest. Ophthalmol Vis. Sci. 37:1124, 1996; Gregory, C. Y. et al., Hum. Mol. Genet. 7:1055–1059, 1996); 6p21.2-cen, for dominant macular degeneration, adult vitelloform (Felbor, U. et al. Hum. Mutat. 10:301–309, 1997); 6p21.1 for dominant cone dystrophy (Payne, A. M. et al. Am. J. Hum. Genet. 61:A290, 1997; Payne, A. M. et al., Hum. Mol. Genet. 7:273–277, 1998; Sokol, I. et al., Mol. Cell. 2:129–133, 1998); 6q, for dominant cone-rod dystrophy (Kelsell, R. E. et al. Am. J. Hum. Genet. 63:274–279, 1998); 6q11–q15, for dominant macular degeneration, Stargardt's-like (Griesinger, I. B. et al., Am. J. Hum. Genet. 63:A30, 1998; Stone, E. M. et al., Arch. Ophthalmol. 112:765–772, 1994); 6q14–q16.2, for dominant macular degeneration, North Carolina Type (Kelsell, R. E. et al., Hum. Mol. Genet. 4:653–656, 1995; Robb, M. F. et al., Am. J. Ophthalmol. 125:502–508, 1998; Sauer, C. G. et al., J. Med. Genet. 34:961–966, 1997; Small, K. W. et al., Genomics 13:681–685, 1992; Small, K. W. et al., Mol. Vis. 3:1, 1997); 6q25–q26, dominant retinal cone dystrophy 1 (Online Mendelian Inheritance in Man (™). Center for Medical Genetics, Johns Hopkins University, and National Center for Biotechnology Information, National Library of Medicine. http://www3.ncbi.nlm.nih.gov/omim (1998); 7p21–p15, for dominant cystoid macular degeneration (Inglehearn, C. F. et al., Am. J. Hum. Genet. 55:581–582, 1994; Kremer, H. et al., Hum. Mol. Genet. 3:299–302, 1994); 7q31.3–32, for dominant tritanopia, protein: blue cone opsin (Fitzgibbon, J. et al., Hum. Genet. 93:79–80, 1994; Nathans, J. et al., Science 193:193–232, 1986; Nathans, J. et al., Ann. Rev. Genet. 26:403–424, 1992; Nathans, J. et al., Am. J. Hum. Genet. 53:987–1000, 1993; Weitz, C. J. et al., Am. J. Hum. Genet. 50:498–507, 1992; Weitz, C. J. et al., Am. J. Hum. Genet. 51:444–446, 1992); not 8q24, for dominant macular degeneration, atypical vitelliform (Daiger, S. P. et al., In ‘Degenerative Retinal Diseases’, LaVail, et al., eds. Plenum Press, 1997; Ferrell, R. E. et al., Am. J. Hum. Genet. 35:78–84, 1983; Leach, R. J. et al., Cytogenet. Cell Genet. 75:71–84, 1996; Sohocki, M. M. et al., Am. J. Hum. Genet. 61:239–241, 1997); 11p12–q13, for dominant macular degeneration, Best type (bestrophin) (Forsman, K. et al., Clin. Genet. 42:156–159, 1992; Graff, C. et al., Genomics, 24:425–434, 1994; Petrukhin, K. et al., Nat. Genet. 19:241–247, 1998; Marquardt, A. et al., Hum. Mol. Genet. 7:1517–1525, 1998; Nichols, B. E. et al., Am. J. Hum. Genet. 54:95–103, 1994; Stone, E. M. et al., Nat. Genet. 1:246–250, 1992; Wadeilus, C. et al., Am. J. Hum. Genet. 53:1718, 1993; Weber, B. et al., Am. J. Hum. Genet. 53:1099, 1993; Weber, B. et al., Am. J. Hum. Genet. 55:1182–1187, 1994; Weber, B. H., Genomics 20: 267–274, 1994; Zhaung, Z. et al., Am. J. Hum. Genet. 53:1112, 1993); 13q34, for dominant macular degeneration, Stargardt type (Zhang, F. et al., Arch. Ophthalmol. 112:759–764, 1994); 16p12.1, for recessive Batten disease (ceroid-lipofuscinosis, neuronal 3), juvenile; protein:Batten disease protein (Batten Disease Consortium, Cell 82:949–957, 1995; Eiberg, H. et al., Clin. Genet. 36:217–218, 1989; Gardiner, M. et al., Genomics 8:387–390, 1990; Mitchison, H. M. et al., Am. J. Hum. Genet. 57:312–315, 1995, Mitchison, H. M. et al., Am. J. Hum. Genet. 56:654–662, 1995; Mitchison, H. M. et al., Genomics 40:346–350, 1997; Munroe, P. B. et al., Am. J. Hum. Genet. 61:310–316, 1997; 17p, for dominant areolar choroidal dystrophy (Lotery, A. J. et al., Ophthalmol. Vis. Sci. 37:1124, 1996); 17p13–p12, for dominant cone dystrophy, progressive (Balciuniene, J. et al., Genomics 30:281–286, 1995; Small, K. W. et al., Am. J. Hum. Genet. 57:A203, 1995; Small, K. W. et al., Am. J. Ophthalmol. 121:13–18, 1996); 17q, for cone rod dystrophy (Klystra, J. A. et al., Can. J Ophthalmol. 28:79–80, 1993); 18q21.1–q21.3, for cone-rod dystrophy, de Grouchy syndrome (Manhant, S. et al., Am. J. Hum. Genet. 57:A96, 1995; Warburg, M. et al., Am. J. Med. Genet. 39:288–293, 1991); 19q13.3, for dominant cone-rod dystrophy; recessive, dominant and ‘de novo’ Leber congenital amaurosis; dominant RP; protein: cone-rod otx-like photoreceptor homeobox transcription factor (Bellingham, J. et al., In ‘Degenerative Retinal Diseases’, LaVail, et al., eds. Plenum Press, 1997; Evans, K. et al., Nat. Genet. 6:210–213, 1994; Evans, K. et al., Arch. Ophthalmol. 113:195–201, 1995; Freund, C. L. et al., Cell 91:543–553, 1997; Freund, C. L. et al., Nat. Genet. 18:311–312, 1998; Gregory, C. Y. et al., Am. J. Hum. Genet. 55:1061–1063, 1994; Li, X. et al., Proc. Natl. Acad. Sci USA 95:1876–1881, 1998; Sohocki, M. M. et al., Am. J. Hum. Genet. 63:1307–1315, 1998; Swain, P. K. et al., Neuron 19:1329–1336, 1987; Swaroop, A. et al., Hum. Mol. Genet. In press, 1999); 22q12.1–q13.2, for dominant Sorsby's fundus dystrophy, tissue inhibitors of metalloproteases-3 (TIMP3) (Felbor, U. et al., Hum. Mol. Genet. 4:2415–2416, 1995; Felbor, U. et al., Am. J. Hum. Genet. 60:57–62, 1997; Jacobson, S. E. et al., Nat. Genet. 11:27–32, 1995; Peters, A. et al., Retina 15:480–485, 1995; Stöhr, H. et al., Genome Res. 5:483–487, 1995; Weber, B. H. F. et al., Nat. Genet. 8:352–355, 1994; Weber, B. H. F. et al., Nat. Genet. 7:158–161, 1994; Wijesvriya, S. D. et al., Genome Res. 6:92–101, 1996); and Xp11.4, for X-linked cone dystrophy (Bartley, J. et al., Cytogenet. Cell. Genet. 51:959, 1989; Bergen, A. A. B. et al., Genomics 18:463–464, 1993; Dash-Modi, A. et al., Invest. Ophthalmol. Vis. Sci. 37:998, 1996; Hong, H.-K., Am. J. Hum. Genet 55:1173–1181, 1994; Meire, F. M. et al., Br. J. Ophthalmol. 78:103–108, 1994; Seymour, A. B. et al., Am. J. Hum. Genet. 62:122–129, 1998), the teachings of which are incorporated herein by reference. In addition, the world wide web site http://WWW.SPH.UTH.TMC.EDU/RETNET/disease.htm lists genetic polymorphisms for macular degeneration and for additional retinal degenerations that also may be associated with macular degeneration. However, none of the above genes or polymorphisms has been found to be responsible for a significant fraction of typical late-onset macular degeneration.
“Environmental” conditions may modulate the rate at which an individual develops AMD or the severity of the disease. Light exposure has been proposed as a possible risk factor, since AMD most severely affects the macula, where light exposure is high. (Young, 1988; Taylor, et al., 1990; Schalch, 1992). The amount of time spent outdoors is associated with increased risk of choroidal neovascularization in men, and wearing hats and/or sunglasses is associated with a decreased incidence of soft drusen (Cruickshanks, et al., 1993). Accidental exposure to microwave irradiation has also been shown to be associated with the development of numerous drusen (Lim, et al., 1993). Cataract removal and light iris pigmentation has also been reported as a risk factor in some studies (Sandberg, et al., 1994). This suggests that: 1) eyes prone to cataracts may be more likely to develop AMD; 2) the surgical stress of cataract removal may result in increased risk of AMD, due to inflammation or other surgically-induced factors; or 3) cataracts prevent excessive light exposure from falling on the macula, and are in some way prophylactic for AMD. While it is possible that dark iris pigmentation may protect the macula from light damage, it is difficult to distinguish between iris pigmentation alone and other, cosegregating genetic factors which may be actual risk factors.
Dietary factors may also influence an individual's risk of developing AMD. Anecdotal evidence from Japan suggests that the incidence of AMD, while very low 20 years ago, has increased as urban Japanese acquired a more Western diet and lifestyle (Bird, 1997). Chemical exposure (Hyman, et al., 1983), smoking (Vingerling, et al., 1996), cardiovascular disease/atherosclerosis (Hyman, et al., 1983; Vingerling, et al., 1995; Blumenkranz, et al., 1986), hypertension (Christen, et al., 1997), dermal elastotic changes in non-sun exposed skin (Blumenkranz, et al., 1986), dietary fat intake (Mares-Perlman, et al., 1995b), low concentrations of serum lycopene (Mares-Perlman, et al., 1995a), and alcohol consumption (Ritter, et al., 1995) have been identified, in some studies, as additional risk factors for the development of wet and/or dry AMD. One recent prospective dietary study found that it is often possible to increase macular pigment density and/or serum concentrations of lutein and zeaxanthin by dietary intake (Hammond, et al., 1997), although the significance of this alteration in modulating macular disease remains to be determined. Thus, dietary consumption of some vegetables, (e.g., spinach, collard greens, kale) may be inversely associated with the risk of developing AMD (Seddon, et al., 1994), an effect which is presumably due to their lutein and zeaxanthin content.
Currently, there is no therapy that is capable of significantly slowing the degenerative progression of AMD, and treatment is limited to laser photocoagulation of the subretinal neovascular membranes that occur in 10–15% of affected patients, which may halt the progression of the disease but does not repair the damage or improve vision. A few clinical studies have shown that drusen regress and that visual acuity improves in some cases, following laser photocoagulation (Sigelman, 1991; Little, et al., 1997; Figueroa, et al., 1994; Frenneson and Nilsson, 1996). While prophylactic laser treatment may be helpful for some patients (Little, et al., 1997), it appears that other patients react adversely to laser treatment of the macula (Hyver, et al., 1997). In addition, while there may be long term benefits for the patient following photocoagulation, these may not be worth the loss of vision frequently associated with this procedure. Indocyanine green angiography is a promising imaging tool that may help identify those patients likely to benefit from laser therapy.
Better understanding of the biology of AMD may allow the development of therapies that can alter the natural history of the disease, serving to halt or reverse its progression. It is understood in the medical arts that any therapeutic intervention is more likely to have a beneficial effect on a patient if undertaken before irreversible pathological changes have occurred. In AMD, however, there exists no readily undertaken screening test that can identify those individuals at risk for developing the disease or for experiencing its unremitting progression. Early identification of AMD could also permit early intervention with greater likelihood of success using established or experimental treatment modalities, including photocoagulation or other techniques familiar to skilled artisans in ophthalmology. Discerning various phenotypes of AMD may identified that respond notably better or worse to a particular method of local treatment, and treatments may be selected accordingly. If the biological basis for certain phenotypes of AMD can be identified, then preventive measures may be undertaken to forestall the onset of the disease or to attenuate its progression. Hence, there exists a need in the art for diagnostic methods adapted for early detection of the disorder when it may still be at a stage amenable to therapeutic intervention.
Further, if the pathophysiological mechanisms for the disease can be elucidated, they can be compared to those mechanisms at work in diseases that appear to coexist with AMD with statistically significant frequency. Then, as therapies are identified for those coexistent diseases, there will be a rational basis for applying those same therapies or their analogues to treat AMD. Thus there exists a need for determining those pathological mechanisms that AMD shares with other disease entities, and a further need for using research in other fields of medicine to apply in the treatment of AMD. As common mechanisms for co-existent diseases are understood, it would be desirable to formulate therapies that beneficially affect the co-existent disease and the AMD, either by preventing the onset of the ocular disorder or by limiting its progression.
A method for diagnosing risk for AMD would permit the clinician to undertake those dietary, environmental or lifestyle interventions that may prevent the onset of the disease or limit its progress. For example, eliminating certain risk factors such as smoking and hypertension from the patient's lifestyle may positively affect the patient's likelihood of developing AMD, or may limit the severity of the disease. Determining an increased risk for developing AMD would provide the patient motivation for making difficult, though healthful, lifestyle choices, or would provide motivation for modifying her or his environment to minimize the risk of developing the disease. Further, determining an increased risk for developing AMD might provide for the patient a rational basis for undertaking other nutritional modifications or supplementations, such as increasing intake of vegetables, vitamins, minerals or nutriceuticals, that may decrease the likelihood of developing AMD or may decrease the severity of its progression. Susceptible individuals could then be targeted for improved health promotion and disease prevention measures for this disabling and highly prevalent disorder.